Global burden of rheumatoid arthritis among adolescents and young adults aged 10–24 years: A trend analysis study from 1990 to 2019

Background In recent decades, there has been a global increase in the burden of rheumatoid arthritis (RA) among adolescents and young adults (AYAs), making it a significant public health issue. However, our understanding of the disease burden, harm, and influencing factors of RA in this population remains insufficient. This study aimed to assess the trends in RA burden among AYAs aged 10–24 years from 1990 to 2019 at the global, regional, and national levels. Methods Incidence, prevalence, and disability-adjusted life years (DALYs) rate per 100,000 population, as well as average annual percentage changes (AAPCs), of RA among individuals aged 10–24 years were reported globally, regionally, and nationally based on the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019). These global trends were further analyzed by age, sex, and Sociodemographic index (SDI). Joinpoint regression analysis was used to determine the year in which the most significant changes in global trends occurred. Results Globally, the incidence of RA among AYAs increased from 4.98 per 100,000 population in 1990 to 5.41 per 100,000 population in 2019, with an AAPCs of 0.29 (95%CI: 0.26, 0.32, p < 0.001). The most significant increase occurred in 2000, while the most significant decrease occurred in 2014. The prevalence increased from 34.11 per 100,000 population in 1990 to 36.34 per 100,000 population in 2019, with an AAPCs of 0.22 (95%CI: 0.19, 0.24, p<0.001); The most significant increase was observed in 2000, and the most significant decrease occurred in 2014. DALYs rate with RA were 5.96 per 100,000 population in 1990 and 5.79 per 100,000 population in 2019 for AYAs, with an average decrease of 0.1 years per year (AAPCs = -0.1, 95%CI: -0.2, -0.01, p = 0.04). In terms of gender, the incidence, prevalence, and DALYs rate were higher for females compared to males during the same period. Regarding age, the incidence, prevalence, and DALYs rate increased with increasing age. Based on the SDI quintile, the incidence, prevalence, and DALYs rate of RA were highest in countries with high SDI and lowest in countries with low SDI from 1990 to 2019. However, the relationship between incidence and SDI is non-linear. In terms of regions, Tropical Latin America exhibited the highest incidence, prevalence, and DALYs rate, while Andean Latin America experienced the most rapid increase in incidence and prevalence. Southern Latin America saw the fastest growth in DALYs rate, whereas Southern Sub-Saharan Africa witnessed the most significant decline. Conclusion In conclusion, the study revealed an overall increase in the incidence and prevalence of RA among adolescents and young adults (AYAs) over the past three decades, while DALYs rate remained relatively stable. Furthermore, the incidence, prevalence, and DALYs rate of RA were found to increase with age. Fortunately, recent proactive preventive measures and treatment methods have shown promising results. Moving forward, it is crucial to prioritize the female population and AYAs patients in order to further alleviate the global burden of RA.


Introduction
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and joint damage, leading to pain, disability, and decline quality of life.Although RA is commonly associated with older adults, recent evidence suggests that it also affects a substantial number of adolescents and young adults (AYAs) [1,2].Over the past few decades, the burden of RA among AYAs has increased globally, making it a significant public health issue.The National Health Interview Survey (NHIS) in the United States estimates that the annual prevalence of arthritis among individuals under the age of 25 is 1.3%, indicating that there are nearly 400,000 children, adolescents, and young adults affected by arthritis in the United States [3].
Studies have shown that patients with RA require ongoing medical care and medication, which not only increases medical expenses, but also leads to a loss of work ability and quality of life.In addition, young people with RA may develop complications such as cardiovascular disease, mental health problems, often resulting in missing school.In severe cases, these complications can result in long-term physical disabilities that persist into adulthood [4].Despite advances in treatment with disease-modifying anti-rheumatic drugs and biologics, most AYAs with RA continue to experience active disease in adulthood, further increasing the cost of treatment and management [5].Socioeconomic inequality, characterized by disparities in income, education level, and access to healthcare services, has been shown to influence health outcomes for various diseases [6][7][8].Multiple studies support a positive association between low-income, low socioeconomic status, or low educational status and non-communicable diseases [7].However, Safiri S et al. [9] found that social development index was non-linear correlated with age-standardized DALYs in rheumatoid arthritis.Until now, the specific impact of socioeconomic inequality on the burden of RA among AYAs remains understudied.Therefore, it is crucial to pay attention to the prevention, diagnosis, and treatment of RA in this vulnerable population.
In this study, we comprehensively assessed the global burden and trends of RA among individuals aged 10-24 years in 204 countries and territories, taking into account factors such as geographical region and socio-demographic development.The findings of this study contribute to the existing literature by providing valuable information for healthcare policies and resource allocation, as well as guiding the development of prevention and intervention strategies to effectively reduce the disease burden of RA in AYAs.

Study population and data collection
The Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019) was published by the Institute for Health Metrics and Evaluation (IHME), based in the United States [7].All data is open source and available to the public.It is the most comprehensive and detailed study of global diseases, injuries, and risk factors.The GBD 2019 covers 204 countries and territories and estimates the burden of 369 diseases and injuries from 1990 to 2019, including RA.The introduction and estimation methods of GBD 2019 are described in detail in the previous systematic analysis study for the Global Burden of Disease [10].All data used in this study were obtained from publicly available databases; further ethical approval was not required.
The United Nations defines adolescence as the period between the ages of 10 and 19 years [11].However, there is no precise definition of young adult at present, and it is often defined as the age range of 15 to 24 years.In the GBD 2019 database, age groups include 10-14 years, 15-19 years, and 10-24 years.Taking into account the GBD 2019 database age group and the general concept, we define the age group of AYAs as 10-24 years old.Furthermore, a definition of 10-24 years corresponds more closely to adolescent growth and popular understandings of this life phase and would facilitate extended investments across a broader range of settings [12].Following the definition of the GBD project, we grouped data on RA based on the age group of 10-24 years and 21 geographically close and epidemiologically similar country regions to provide a more detailed description of the disease burden of RA among patients in this age range.The 21 geographic regions include: Andean Latin America, Australasia Caribbean, Central Asia, Central Europe Central Latin America, Central Sub-Saharan Africa, East Asia, Eastern Europe, Eastern Sub-Saharan Africa, High income Asia Pacific, High income North America, North Africa and Middle East, Oceania, South Asia, Southeast Asia, High income Asia Pacific, High income North America, North Africa and Middle East, Oceania, South Asia, Southeast Asia, Southern Latin America, Southern Sub-Saharan Africa, Tropical Latin America, Western Europe, and Western Sub-Saharan Africa.
The study focused primarily on the trends of three indicators: incidence, prevalence, and disability-adjusted life years (DALYs).DALYs, a measure of disease burden, combines years of life lost due to premature mortality and years lived with disability caused by the disease.The DALYs of RA in AYAs group were calculated using the relevant data provided by GBD 2019, and the trend was further analyzed.
The GBD 2019 also calculated the sociodemographic index (SDI) for each country, which is a composite measure of social and economic conditions that influence health outcomes in each region.SDI measures the overall economic development of a society based on indicators such as education level, per capita income, and fertility rate.The SDI ranges from 0 to 1, with higher values representing higher levels of socioeconomic development.SDI is divided into five quintiles: low, low-middle, middle, high-middle, and high [10].The relationship between the SDI and the incidence in different countries and regions was analyzed in this study.

Statistical analysis
The data analysis method used in this paper refers to the method of Zhang Jing et al [13].Incidence, prevalence, and DALYs rate for RA in AYAs were obtained from the cross-sectional data of GBD 2019, which provided estimates with 95% uncertainty intervals (UI), representing the 25th and 975th ordered estimates derived from 1,000 draws from the posterior distribution.Age-specific ratios and their annual mean percentage changes (AAPCs) were calculated by linear regression using the logarithm of the ratio on a logarithmic scale as the dependent variable and the year as the independent variable.AAPCs is a summary measure of the trend over a pre-specified fixed interval, calculated as the weighted average of the annual percent changes (APCs), allowing us to describe the average APCs over the study period with a single number.The value of AAPCs represents the annual percentage change (increase, decrease, or no change).For example, if the AAPCs is 0.1, it means there is a 0.1% increase in the annual growth rate.The trend in the incidence was reflected in the AAPCs value and its 95% confidence interval.The AAPCs for incidence, prevalence, and DALYs rate from 1990 to 2019 were calculated.Additionally, the years with the most substantial changes in trends for the aforementioned indicators were determined.Joinpoint regression analysis was employed to identify trends in the data over time, with the simplest model being fitted by connecting several different line segments on a logarithmic scale.These segments, known as joinpoints, were tested using a Monte Carlo permutation method.The final model was selected using the weighted Bayesian information criteria method and the suggestions provided by Joinpoint software.Global trends were analyzed, and stratified analyses of these trends were conducted by age group, gender, and SDI.The methodology used in AAPCs calculations was the same as described above.All statistical analyses were performed using RStudio software (version 4.3.1)and the Joinpoint Regression Program (version 5.0.2).
The joint point regression analysis of the changing trend of the prevalence found that the prevalence of RA among AYAs had great changes in 1997,2000,2009,2014
Joint point regression analysis found substantial changes in RA DALYs in the AYAs population in 1996, 1999, 2009, 2014 and 2017, with the largest change in 2014 (Fig 3C ).

Effects of different SDI on Incidence rate
At the regional level, there is a nonlinear relationship between the incidence rate and SDI.With the improvement of SDI, it rises and falls intermittently (Fig 4).During the period from 1990 to 2019, the super-regions of Western Europe, High-income North America, and High-income Asia Pacific showed an upward trend.All regions in the Latin American super-region showed an upward trend during the period from 1990 to 2019, and were higher than expected.During the period from 1990 to 2019, the incidence rates in East Asia, Eastern Europe, North Africa and the Middle East, Southeast Asia, Oceania, and High-income Asia Pacific were lower than expected (Fig 4A ).
The analysis at the national level found that there is a nonlinear relationship between the incidence rate and SDI, and the high burden of RA not only exists in developed countries, but also in underdeveloped countries.The incidence rates in Puerto Rico, the UK, Uzbekistan, Brazil, Uzbekistan, Honduras, Nicaragua, Pakistan, Nepal, and many other countries are much higher than expected.In contrast, many countries, such as Norway, the United Arab Emirates, Qatar, Sri Lanka, Nigeria, Senegal, have lower than expected incidence rates (Fig 4B ).

Discussions
RA is a chronic inflammatory condition that not only affects the musculoskeletal system but also has negative impacts on multiple systems and organs in the body, as highlighted in several studies [1,[14][15][16].Therefore, early intervention and treatment for RA in AYAs is of utmost importance.Several studies have investigated the global burden and trends of RA in adolescents and young adults [9,17], but to our knowledge, this study is the first systematic evaluation of the global burden and trends of RA in adolescents and young adults across 204 countries and territories from 1990 to 2019.
The study revealed that in 2019, the global incidence of RA in adolescents was 5.41 per 100 000 population, and the prevalence was 36.34 per 100 000 population.Compared to 1990, these rates increased by 8.63% and 6.54%, respectively.Although there was a slight decrease of 2.94% in DALYs rate between 1990 and 2019, the change was not statistically significant.Overall, the trend of RA incidence and disease burden in the adolescent population remains concerning, necessitating more effective intervention measures to curb this phenomenon and reduce future disease burden.Analysis of the incidence, prevalence, and DALYs rate of RA in different genders and age groups among adolescents revealed that females had higher incidence and prevalence as well as DALYs rate compared to males.This is consistent with the findings of studies conducted by Guan S. et al [2] and Safiri S. et al [9].Similar gender disparities were also found in middleaged and older populations.It is well-documented that autoimmune diseases are more common in females, and they are the fourth leading cause of disability in women [18,19].This may be related to sex hormones, as androgens have been shown to suppress humoral and cellular immune responses, while estrogens enhance humoral immune responses [20].A study of 105 303 men with prostate cancer found that those who received androgen deprivation therapy had a 23 percent increase in RA diagnoses over five years [21].Another study on RA patients found lower levels of androgens (testosterone, dihydrotestosterone, and dehydroepiandrosterone sulfate) in their body fluid, suggesting that reduced androgen levels increase the risk of RA diagnosis [22].Therefore, in formulating policies for the prevention and treatment of RA, greater attention should be paid to the female population.Additionally, androgen intervention may become a useful treatment measure for RA.
When analyzing the relationship between SDI and incidence rates in different regions and countries, it was found that the relationship between the incidence of rheumatoid arthritis (RA) in the adolescent population and SDI exhibits a complex nonlinear association.The burden of RA is not limited to developed or underdeveloped countries, and there are reports of high RA burdens in various SDI countries.The differences in RA burden among different SDI regions are consistent with the findings of Guan SY et al. [2].Safiri S et al. also discovered this complex nonlinear relationship when analyzing the global burden of rheumatoid arthritis through the GBD 2017 [9].Even within the same super-region, there are differences in RA incidence rates among different regions or countries.In Southeast Asia, including Cambodia and Thailand, the incidence rates are relatively low, while in South Asia, such as India and Pakistan, the incidence rates are relatively high.Currently, there is no clear evidence to provide a reasonable explanation for this phenomenon.Potential trends in environmental risk factors and differences in medical policies among different countries may affect the incidence of RA [23].Smoking, as one of the important risk factors, requires precise monitoring and specific prevention plans to be developed by each country.Whether other potential risk factors, such as obesity, intestinal microbiota, diet, and genetic factors, will affect the incidence of RA still requires further research [9,24].
Although the overall trend of the incidence and prevalence of RA in adolescents and young adults has been increasing from 1990 to 2019, a significant inflection point occurred in 2014 when the trend shifted from an upward trajectory to a downward trend, representing the largest change in the 30-year period.The decline in DALYs rate was slight since 2009, with the largest decrease also observed in 2014.Overall, there has been little significant change in DALYs rate from 1990 to 2017.The magnitude of DALYs largely depends on the effectiveness of RA treatment and the importance of early intervention.Over the past few decades, the treatment of RA has evolved to emphasize the importance of early intervention, and newer and more effective drugs have been applied to patients, effectively limiting disease activity, radiographic progression, and functional loss [25][26][27].A Norwegian study found a general decline in the incidence of joint replacement, joint fusion, and synovectomy among RA patients between 1997 and 2012.The general increasing trend in the use of synthetic and biological disease-modifying antirheumatic drugs (DMARDs) is consistent with less joint destruction and improved long-term outcomes in RA patients [28].However, due to the higher costs involved, the benefits of this may be more evident in high-income regions.Early diagnosis and treatment can prevent the progression of joint damage in 90% of early RA patients [26].In underdeveloped regions, the lack of standardized diagnosis makes it difficult to diagnose RA early.Delayed diagnosis of RA in these regions may hinder effective treatment and eventually lead to RA-related disabilities.Therefore, it is crucial to raise awareness of the burden of RA in underdeveloped regions and improve outcomes by implementing early clinical diagnosis and utilizing relatively low-cost drugs, such as methotrexate, to manage the disease, prevent RA-related complications, and reduce the burden and adverse consequences of RA [9].
The study has several limitations.Firstly, the data for this research relies on the GBD 2019 database.Therefore, the quality of this study is subject to limitations such as variations in the quality and availability of GBD 2019 data.The data collected from different regions and countries may differ in terms of quality, comparability, accuracy, and extent of missing data.Secondly, various countries, particularly underdeveloped ones, may face challenges in effectively screening, assessing, and treating RA.This can restrict the representativeness of the statistical data.

Conclusion
This study found an overall increase in the incidence and prevalence of RA among AYAs over the past 30 years, while DALYs rate have remained virtually unchanged.In addition, the incidence, prevalence and DALYs rate of RA increased with the increase of age.Fortunately, recent proactive preventive measures and treatment methods have shown promising results.In the future, it is necessary to pay more attention to female populations and AYAs patients in order to further reduce the global burden of RA.

Fig 1
summarizes the global incidence of RA in AYAs at the country level in 2019.The countries with the lowest incidence of RA in AYAs in 2019 were Chad (1.37 per 100 000 Fig 2 shows the rate of change in the number of new cases in different countries from 1990 to 2019.Qatar topped the list with a 523% increase, followed by Equatorial Guinea with a 413% increase.Forty-six countries saw a decline in the number of new cases of RA among AYAs from 1990 to 2019, with a 48% decline in Georgia and a 43% decline in Bulgaria.The joint point regression analysis found substantial changes in the incidence of RA in 1996, 2000, 2007, 2014 and 2017, with the largest change occurring in 2014 (Fig 3A).

Fig 4 .
Fig 4. The association between the incidence of RA among AYAs and SDI at the regional level from 1990 to 2019 (A) and national level at 2019 (B).RA = rheumatoid arthritis.AYAs = adolescents and young adults.SDI = social development index.https://doi.org/10.1371/journal.pone.0302140.g004